Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial–temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 patients with urothelial carcinoma. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of urothelial carcinoma. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multiregional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. ecDNA is present in 36% of urothelial carcinoma tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of MHC class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment–derived DNA has excellent specificity in detecting ecDNA. Significance: Our comprehensive analysis of ecDNA in urothelial carcinoma reveals its crucial role in driving the evolution and heterogeneity of multifocal cancer, as well as its early involvement in tumorigenesis. Moreover, this study sheds light on immune evasion mechanisms associated with ecDNA and offers valuable insights for developing targeted therapeutic strategies.

Rationale: Extrachromosomal circular DNA is a hallmark of cancer, but its role in shaping the genome heterogeneity of urothelial bladder carcinoma (UBC) remains poorly understood. Here, we comprehensively analyzed the features of extrachromosomal circular DNA in 80 UBC patients.

Objective: This study was performed to evaluate the application of enhanced recovery after surgery (ERAS) in patients undergoing radical cystectomy (RC). Methods: The clinical data of 192 patients who underwent RC were collected in this retrospective cohort study. Among them, 91 patients who underwent ERAS were allocated to the ERAS group, and the remaining 101 patients who underwent traditional postoperative care procedures were allocated to the non-ERAS group. Perioperative indexes in the two groups were compared. The ERAS components included rehabilitation exercise, carbohydrate fluid loading, cessation of nasogastric tubes, omission of oral bowel preparation, regional local anesthesia, body-warming procedures, reduced drainage use, and early postoperative drinking and eating. Results: The times from RC to first water intake, first ambulation, first anal exhaust, first defecation, and pelvic drainage tube removal were significantly shorter and the hospitalization costs were significantly lower in the ERAS than non-ERAS group. The intraoperative blood loss volume, blood transfusion rate, readmission rate, and incidence of postoperative complications were also significantly lower in the ERAS than non-ERAS group. Conclusion: ERAS may effectively accelerate patient rehabilitation and reduce the length of stay, incidence of postoperative complications, readmission rates, and hospitalization costs for patients undergoing RC.

Amplification of amino acids synthesis is reported to promote tumorigenesis. The serine/glycine biosynthesis pathway is a reversible conversion of serine and glycine catalyzed by cytoplasmic serine hydroxymethyltransferase (SHMT)1 and mitochondrial SHMT2; however, the role of SHTM1 in renal cell carcinoma (RCC) is still unclear. We found that low SHMT1 expression is correlated with poor survival of RCC patients. The in vitro study showed that overexpression of SHMT1 suppressed RCC proliferation and migration. In the mouse tumor model, SHMT1 significantly retarded RCC tumor growth. Furthermore, by gene network analysis, we found several SHMT1‐related genes, among which homeobox D8 (HOXD8) was identified as the SHMT1 regulator. Knockdown of HOXD8 decreased SHMT1 expression, resulting in faster RCC growth, and rescued the SHMT1 overexpression‐induced cell migration defects. Additionally, ChIP assay found the binding site of HOXD8 to SHMT1 promoter was at the −456~−254 bp region. Taken together, SHMT1 functions as a tumor suppressor in RCC. The transcription factor HOXD8 can promote SHMT1 expression and suppress RCC cell proliferation and migration, which provides new mechanisms of SHMT1 in RCC tumor growth and might be used as a potential therapeutic target candidate for clinical treatment.

Background: Lymph node metastasis is the most unfavorable prognostic factor of penile squamous cell carcinoma (PSCC). However, patients with the same lymph node status have different outcomes, and molecular classifiers for precise prognostic assessments are lacking.

Yin GN, et al. Investig Clin Urol. 2020 Aug;62:e8. https://doi.org/10.4111/icu.20200272